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Biomedical subjects

E Braunwald

Publications and source records attributed to E Braunwald.

At least 271 records · Page 15Linked to original sources
PubMed1986

Milrinone and dobutamine in severe heart failure: differing hemodynamic effects and individual patient responsiveness.

Milrinone and dobutamine were compared in 15 patients with New York Heart Association functional class III and IV congestive heart failure. Dobutamine and milrinone were administered intravenously according a graded titration schedule up to maximum doses (14 micrograms/kg/min and 75 micrograms/kg, respectively) or until increased ventricular ectopy or a reduction in left ventricular end-diastolic pressure to 10 mm Hg or less occurred. Although both agents markedly increased cardiac index, milrinone caused a significantly greater reduction in left and right heart filling pressures and mean arterial pressure than did dobutamine, and for any given increase in dP/dt, milrinone caused a greater reduction in systemic vascular resistance than did dobutamine. Thus, the hemodynamic effects of milrinone are best represented by a combination of the actions of dobutamine, a positive inotropic agent, and a vasodilator such as nitroprusside, which causes both arterial and venous dilation. The positive inotropic responses of individual patients to dobutamine (5 micrograms/kg/min) and milrinone (25 micrograms/kg) were compared. The increases in dP/dt with both agents were variable, and correlated poorly (r = .50; p = .059). Patients were divided into two groups: Group I consisted of eight patients in whom the ratio of the increase in dP/dt with dobutamine vs milrinone was greater than 1.0 (good dobutamine responders); group II consisted of seven patients in whom this ratio was less than 1.0 (poor dobutamine responders).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1985

Experimental and clinical observations on the efficacy of esmolol in myocardial ischemia.

Beta blockers reduce myocardial oxygen demand and are therefore useful in ischemic states. They reduce angina pectoris and reduce the risk of death when administered long-term after acute myocardial infarction. Some studies suggest that when administered early after coronary occlusion they can reduce myocardial infarct size. Relative contraindications to beta blockers, such as a history of congestive heart failure, chronic obstructive lung disease, atrioventricular conduction defects and low blood pressure, limit their use. Conventional beta blockers have a relatively long duration of action and are either contraindicated or must be used with particular caution in patients with these contraindications. Esmolol is an ultrashort-acting beta blocker with a biologic half-life of 9 minutes. Therefore, such an agent may be useful in patients with ischemic heart disease in whom reducing heart rate would be beneficial but in whom there is concern that beta blockers might not be tolerated. Esmolol reduced myocardial infarct size in 2 experimental studies of coronary occlusion followed by reperfusion, and improved the recovery of the stunned myocardium when administered during experimental myocardial ischemia. Esmolol's brief duration of action may make it safer than conventional beta blockers for the management of patients with unstable angina or myocardial infarction.

Adrenergic beta-Antagonists↗
PubMed1985

Effect of intracoronary verapamil on infarct size in the ischemic, reperfused canine heart: critical importance of the timing of treatment.

In an effort to determine whether the beneficial effect of calcium blocking drugs occurs only during ischemia or during reperfusion as well, anesthetized dogs were subjected to 3 hours of occlusion of the left anterior descending coronary artery followed by 3 hours of reperfusion. In protocol A, intracoronary verapamil (0.01 mg/kg/min) was begun 90 minutes after coronary occlusion and continued for 1 hour into the reperfusion phase (n = 6) while a control group received an infusion of saline solution (n = 6). In vivo area at risk determined by dye injection was 29 +/- 3% of the left ventricle (+/- standard error of the mean) in the control group and 30 +/- 3% in the verapamil group (difference not significant [NS]), whereas the area of necrosis determined by triphenyltetrazolium staining and expressed as a percent of area at risk was smaller in the verapamil group (29 +/- 8%) than in the control group (57 +/- 8%, p less than 0.05). In protocol B, verapamil infusion into the left anterior descending coronary was begun 5 minutes before blood reperfusion and continued throughout the 3-hour reperfusion phase. Area at risk was similar in both groups (control, 25 +/- 1%, n = 8; verapamil, 28 +/- 2%, n = 8, NS); area of necrosis expressed as a percentage of area at risk was 49 +/- 6% in the control group and 45 +/- 10% in the verapamil group (NS). Therefore, calcium blockade of ischemic myocytes delays death and enhances salvage produced by reperfusion. However, calcium blockade begun after prolonged coronary occlusion does not enhance reperfusion-induced myocardial salvage.

Animals↗
PubMed1985

Physiologic assessment of the inotropic, vasodilator and afterload reducing effects of milrinone in subjects without cardiac disease.

Milrinone increases left ventricular (LV) shortening. Whether these changes result from vasodilation alone or from a combination of vasodilation and a positive inotropic action is controversial. Load-independent end-systolic indexes of LV contractility were measured over a wide range of aortic pressures generated by methoxamine infusion before and during milrinone administration. Sixteen studies were performed using echocardiography and calibrated carotid pulse tracings in 11 normal subjects. Milrinone loading doses of 30, 45 or 60 micrograms/kg were given intravenously over 10 minutes, followed by a maintenance infusion to achieve steady-state drug levels. Milrinone induced a dose-dependent decrease in baseline (i.e., before methoxamine) total systemic resistance (p less than 0.05) and afterload as measured by end-systolic wall stress (p less than 0.001). The associated changes in the end-systolic pressure-dimension, stress-shortening and stress-velocity of fiber shortening relations were characteristic of a positive inotropic intervention. All end-systolic indexes of LV contractility demonstrated greater inotropic effect at the higher milrinone plasma concentrations. Thus, load-independent indexes of LV contractility show that milrinone has a dose-related positive inotropic effect separate from its vasodilator (total systemic resistance) and afterload (end-systolic stress) reducing effects.

Adolescent↗
PubMed1985

Effects of transient increased afterload during experimentally induced acute myocardial infarction in dogs.

Alterations in afterload may occur during acute myocardial infarction (AMI), but it is unknown whether such alterations cause long-term changes in the left ventricular topography or alter healing of the AMI. AMI was produced by ligation of the left anterior descending coronary artery in open-chest dogs. Eight dogs were randomized to a methoxamine group with an infusion dose of 30 micrograms/kg/min starting 1 hour after ligation for 4 hours to increase systemic systolic pressure by 40 to 50 mm Hg, and 8 were randomized to a saline control group (n = 8). Seven days later the dogs were killed and the hearts examined. The ratio of infarct wall thickness to noninfarct wall thickness was 1.13 +/- 0.03 (mean +/- standard error of the mean) in control dogs and was 0.98 +/- 0.03 in the dogs treated with methoxamine (p less than 0.005). An expansion index was determined as previously reported and expansion was considered to have occurred if this index exceeded 1.09. The expansion index was 0.98 +/- 0.06 in the control group and 1.18 +/- 0.07 in the methoxamine group (p less than 0.05). Histologic analysis suggested a lag in the healing rate in the methoxamine-treated dogs. Thus, early, brief increases in afterload cause infarct expansion and thinning and appears to slow the early healing phase of AMI in dogs.

Animals↗
PubMed1985

The futility index. An approach to the cost-effective termination of randomized clinical trials.

Although the randomized clinical trial is recognized as the method of choice for evaluating therapeutic innovations, it is often enormously expensive--in some instances, as a result of the unnecessary continuation of a trial destined to conclude that an innovation is not superior to standard therapy. Although most large clinical trials in which results evolve over time are monitored for early evidence of efficacy or toxicity, trials are rarely terminated because the probability of a positive result regarding the value of the innovation has become low. This paper discusses the issues involved in the monitoring and early termination of long-term clinical trials and describes the futility index, a probabilistic basis for early termination of trials of innovative therapy when the accumulated data imply small probability of success. Utilization of the futility index in the management of clinical trials of innovations can be of value in reducing, at slight loss of power, the number of unproductive studies carried to completion, thereby creating new opportunities for more effective use of limited resources.

Clinical Trials as Topic↗
PubMed1985

High dose intravenous streptokinase for acute myocardial infarction: preliminary results of a multicenter trial.

To assess the efficacy of intravenous streptokinase in patients with acute myocardial infarction, 40 patients (30 men and 10 women, mean age 54 years) with acute myocardial infarction were given 1.5 million U of streptokinase intravenously in 1 hour, and coronary arteriography was performed repeatedly to assess reperfusion. Streptokinase treatment was begun 270 +/- 86 (mean +/- SD) minutes after the onset of chest pain. Of the 40 patients, 34 had total or near total coronary occlusion before streptokinase administration. In 14 (41%) of these 34 patients, some reperfusion occurred during the 90 minutes after the administration of streptokinase, but in only 11 of the 14 was reperfusion present at 90 minutes. After streptokinase administration, all patients received heparin for 8 to 10 days; they were subsequently administered aspirin and dipyridamole. Clinical evidence of reocclusion during the first 24 hours of heparin therapy occurred in one patient. Thus, when given to patients with acute myocardial infarction and total coronary occlusion an average of 4 1/2 hours after the onset of chest pain, high dose intravenous streptokinase achieves reperfusion in only about 40% and results in sustained reperfusion in only about 30%.

Adult↗
PubMed1985

Inotropic stimulation of reperfused myocardium with dopamine: effects on infarct size and myocardial function.

Prolonged postischemic ventricular dysfunction ("stunned myocardium") may be responsible for heart failure after myocardial reperfusion. Although inotropic stimulation can enhance the contractility of stunned myocardium, it could potentially increase infarct size and thereby impair ultimate recovery of myocardial function. In 16 anesthetized dogs, the left anterior descending coronary artery was occluded for 2 hours, and then reperfused. At 45 minutes of reperfusion, the dogs were randomized to receive a 3 hour intravenous infusion of either saline solution or dopamine (10 micrograms/kg per min), and 1 hour after the infusion was discontinued the area of necrosis and an in vivo area at risk of necrosis were determined. All dogs had serial two-dimensional echocardiograms with computer-assisted analysis and in vivo biopsies for determination of adenosine triphosphate and creatine phosphate levels. Dopamine caused an increase in the contractility of the reperfused myocardium, with systolic wall thickening increasing from -4.1 +/- 2.6 (mean +/- SEM) to +24.0 +/- 3.7% (p less than 0.002) and short-axis cross-sectional ejection fraction increasing from 27.1 +/- 4.7 to 71.6 +/- 4.4% (p less than 0.002) after 15 minutes of infusion. Regional myocardial blood flow in the previously ischemic epicardium was increased from 1.18 +/- 0.11 ml/min per g with saline to 2.95 +/- 0.36 ml/min per g with dopamine (p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1985

Effects of digitalis on the normal and the failing heart.

Although it has been known for more than a century that digitalis glycosides exert a powerful beneficial effect on patients with heart failure, atrial fibrillation and a rapid ventricular rate, it was believed for many years that the drug exerts this clinical effect primarily by slowing the heart rate. It was also thought that the extra-cardiac vascular actions of digitalis might be responsible for its therapeutic effect. It has now been established that cardiac glycosides cause arteriolar and venous constriction in a variety of mammalian species including human beings, and that this vasoconstriction involves the coronary vascular bed as well, but it is believed that these actions are not responsible for any beneficial clinical effect. A variety of investigations on cardiac muscle in vitro, anesthetized and conscious dogs and anesthetized and conscious human subjects have shown that cardiac glycosides improve the contractility of failing mammalian myocardium. It has become clear that digitalis also stimulates the contractility of the nonfailing heart. The degree of augmentation of contractility induced by cardiac glycosides is related inversely to the baseline contractile state. Myocardial oxygen consumption, which is increased in the normal heart by the positive inotropic action of glycosides, is actually reduced or remains constant in the failing heart. Cardiac glycosides increase the contractility of the globally ischemic heart, but their actions in chronic ischemic heart disease with regional impairment of function are complex. Deterioration of segmental performance occurs in ischemic and necrotic segments, while improvement of contractility occurs in adjacent normal segments.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1985

Use of an ultra short-acting beta-blocker in patients with acute myocardial ischemia.

Esmolol is a new ultra short-acting (half-life [t1/2] beta 9 min) beta 1-adrenergic-receptor antagonist reported to have no intrinsic sympathomimetic activity. The safety and efficacy of esmolol in lowering the ventricular rate and rate-pressure product in patients with acute myocardial infarction (n = 5), postmyocardial infarction angina (n = 10), or acute unstable angina (n = 4), and without cardiogenic shock were studied. After a 30 min observation period, esmolol was titrated to a maximum dose of 300 micrograms/kg/min and infused for up to 420 min. The ventricular rate fell from 92 +/- 11 (mean +/- SD) to 77 +/- 13 beats/min (p less than .01) and the systolic arterial pressure decreased from 120 +/- 13 to 97 +/- 11 mm Hg (p less than .01) during the initial 30 min titration period. There was no significant change during the maintenance phase, and both the ventricular rate and arterial pressure returned rapidly toward baseline values within 30 min of termination of the infusion. The cardiac index fell from 2.8 +/- 0.6 to 2.2 +/- 0.6 liters/min/m2 (p less than .01) during the same period, and also returned to the baseline level 30 min after termination of the infusion. There was no significant change in the pulmonary capillary wedge pressure, respiratory rate, or PR interval. Five patients required termination of infusion because of hypotension and all recovered uneventfully within 30 min of stopping the esmolol. One patient required a brief infusion of dopamine to restore hemodynamic stability.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Influence of chronic captopril therapy on the infarcted left ventricle of the rat.

To determine whether the relationship between infarct size and ventricular performance, volume, and compliance could be altered favorably, captopril was administered to rats for 3 months following coronary artery ligation. Baseline left and right ventricular and systemic arterial pressures and aortic blood flow, and maximal stroke volume and cardiac indices attained during a volume loading, were measured. Passive pressure-volume relations of the left ventricle were determined, and the slopes of segments of this relation were analyzed to characterize ventricular chamber stiffness. In untreated rats, left ventricular end-diastolic pressure progressively rose (from 5-28 mm Hg) as a function of infarct size, whereas, in captopril-treated rats, filling pressure remained within normal limits (5 +/- 1 mm Hg) in all but those with extensive infarcts. Chronic captopril therapy reduced baseline mean arterial pressure and total peripheral resistance, yet maintained cardiac and stroke outputs in rats both with and without infarcts. In untreated rats, maximal pumping ability progressively declined with increasing infarct size, whereas, in captopril-treated rats, peak stroke volume index remained within normal limits in all but those with extensive infarcts. The in vitro left ventricular volumes of captopril-treated rats were significantly less than those of untreated rats. The maintenance of forward output from a lesser dilated left ventricle yielded an index of ejection fraction for treated rats with moderate and large infarcts that was significantly elevated compared with that of untreated rats with infarcts of comparable size. Left ventricular chamber stiffness, which fell as infarct size increased in untreated rats, was normalized by chronic captopril therapy. Thus, captopril attenuated the left ventricular remodeling (dilation) and deterioration in performance that were observed in rats with chronic myocardial infarction.

Animals↗
PubMed1985

Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside.

Milrinone is a potent positive inotropic and vascular smooth muscle-relaxing agent in vitro, and therefore, it is not known to what extent each of these actions contributes to the drug's hemodynamic effects in patients with heart failure. In 11 patients with New York Heart Association class III or IV congestive heart failure, incremental intravenous doses of milrinone were administered to determine the dose-response relationships for heart rate, systemic vascular resistance, and inotropic state, the latter measured by peak positive left ventricular derivative of pressure with respect to time (dP/dt). To clarify further the role of a positive inotropic action, the relative effects of milrinone and nitroprusside on left ventricular stroke work and dP/dt were compared in each patient at doses matched to cause equivalent reductions in mean arterial pressure or systemic vascular resistance, indices of left ventricular afterload. Milrinone caused heart rate, stroke volume, and dP/dt to increase, and systemic vascular resistance to decrease in a concentration-related manner. At the two lowest milrinone doses resulting in serum concentrations of 63 +/- 4 and 156 +/- 5 ng/ml, respectively, milrinone caused significant increases in stroke volume and dP/dt, but no changes in systemic vascular resistance or heart rate. At the maximum milrinone dose administered (mean serum concentration, 427 +/- 11 ng/ml), heart rate increased from 92 +/- 4 to 99 +/- 4 bpm (P less than 0.01), mean aortic pressure fell from 82 +/- 3 to 71 +/- 3 mmHg (P less than 0.01), right atrial pressure fell from 15 +/- 2 to 7 +/- 1 mmHg (P less than 0.005), left ventricular end-diastolic pressure fell from 26 +/- 3 to 18 +/- 3 (P less than 0.005), stroke volume index increased from 20 +/- 2 to 30 +/- 2 ml/m2 (P less than 0.005), stroke work index increased from 14 +/- 2 to 21 +/- 2 g X m/m2 (P less than 0.01), and dP/dt increased from 858 +/- 54 to 1,130 +/- 108 mmHg/s (P less than 0.005). When compared with nitroprusside for a matched reduction in mean aortic pressure or systemic vascular resistance, milrinone caused a significantly greater increase in stroke work index at the same or lower left ventricular end-diastolic pressure. Milrinone caused a concentration-related increase in dP/dt (32% increase at maximum milrinone dose), whereas nitroprusside had no effect. These data in patients with severe heart failure indicate that in addition to a vasodilating effect, milrinone exerts a concentration-related positive inotropic action that contributes significantly to the drug's overall hemodynamic effects. The positive inotropic action occurs at drug levels that do not exert significant chronotropic or vasodilator effects.

Adult↗